LEUSTATIN (cladribine) Injection
should be administered under the supervision of a qualified physician
experienced in the use of antineoplastic therapy. Suppression of bone marrow
function should be anticipated. This is usually reversible and appears to be
dose dependent. Serious neurological toxicity (including irreversible
paraparesis and quadraparesis) has been reported in patients who received
LEUSTATIN Injection by continuous infusion at high doses (4 to 9 times the
recommended dose for Hairy Cell Leukemia). Neurologic toxicity appears to
demonstrate a dose relationship; however, severe neurological toxicity has been
reported rarely following treatment with standard cladribine dosing regimens.

Acute nephrotoxicity has been
observed with high doses of LEUSTATIN (4 to 9 times the recommended dose for
Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic
agents/therapies.

DESCRIPTION

LEUSTATIN (cladribine) Injection (also commonly known as
2-chloro-2'-deoxy- β -D-adenosine) is a synthetic antineoplastic
agent for continuous intravenous infusion. It is a clear, colorless, sterile,
preservative-free, isotonic solution. LEUSTATIN Injection is available in
single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine
nucleoside analog. Each milliliter of LEUSTATIN Injection contains 1 mg of the
active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive
ingredient. The solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or
dibasic sodium phosphate may have been added to adjust the pH to 6.3±0.3.

The chemical name for cladribine is
2-chloro-6-amino-9-(2-deoxy-β-D-erythropentofuranosyl) purine and the
structure is represented below:

INDICATIONS

DOSAGE AND ADMINISTRATION

Usual Dose

The recommended dose and schedule of LEUSTATIN Injection for
active Hairy Cell Leukemia is as a single course given by continuous infusion
for 7 consecutive days at a dose of 0.09 mg/kg/day. Deviations from this dosage
regimen are not advised. If the patient does not respond to the initial course
of LEUSTATIN Injection for Hairy Cell Leukemia, it is unlikely that they will
benefit from additional courses. Physicians should consider delaying or
discontinuing the drug if neurotoxicity or renal toxicity occurs (see WARNINGS).

Specific risk factors predisposing to increased toxicity
from LEUSTATIN have not been defined. In view of the known toxicities of agents
of this class, it would be prudent to proceed carefully in patients with known
or suspected renal insufficiency or severe bone marrow impairment of any
etiology. Patients should be monitored closely for hematologic and
non-hematologic toxicity (see WARNINGS andPRECAUTIONS).

Preparation and Administration of Intravenous Solutions

LEUSTATIN Injection must be diluted with the designated
diluent prior to administration. Since the drug product does not contain any
anti-microbial preservative or bacteriostatic agent, aseptic technique and
proper environmental precautions must be observed in preparation of LEUSTATIN
Injection solutions.

To prepare a single daily dose

LEUSTATIN Injection should be passed through a sterile 0.22μm
disposable hydrophilic syringe filter prior to introduction into the infusion
bag, prior to each daily infusion. Add the calculated dose (0.09 mg/kg or 0.09
mL/kg) of LEUSTATIN Injection through the sterile filter to an infusion bag
containing 500 mL of 0.9% Sodium Chloride Injection, USP. Infuse continuously
over 24 hours. Repeat daily for a total of 7 consecutive days. The use of 5%
dextrose as a diluent is not recommended because of increased degradation of
cladribine. Admixtures of LEUSTATIN Injection are chemically and physically
stable for at least 24 hours at room temperature under normal room fluorescent
light in Baxter Viaflex®† PVC infusion containers. Since limited
compatibility data are available, adherence to the recommended diluents and
infusion systems is advised.

Dose of LEUSTATIN Injection

Recommended Diluent

Quantity of Diluent

24-hour infusion method

1(day) x 0.09 mg/kg

0.9% Sodium Chloride Injection, USP

500 mL

To prepare a 7-day infusion

The 7-day infusion solution should
only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9%
benzyl alcohol preserved). In order to minimize the risk of microbial
contamination, both LEUSTATIN Injection and the diluent should be passed
through a sterile 0.22 μm disposable hydrophilic syringe filter as each
solution is being introduced into the infusion reservoir. First add the
calculated dose of LEUSTATIN Injection (7 days x 0.09 mg/kg or mL/kg) to the
infusion reservoir through the sterile filter.

Then add a calculated amount of
Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol
preserved) also through the filter to bring the total volume of the solution to
100 mL. After completing solution preparation, clamp off the line, disconnect
and discard the filter. Aseptically aspirate air bubbles from the reservoir as
necessary using the syringe and a dry second sterile filter or a sterile vent
filter assembly. Reclamp the line and discard the syringe and filter assembly. Infuse
continuously over 7 days. Solutions prepared with Bacteriostatic Sodium
Chloride Injection for individuals weighing more than 85 kg may have reduced
preservative effectiveness due to greater dilution of the benzyl alcohol
preservative. Admixtures for the 7-day infusion have demonstrated acceptable
chemical and physical stability for at least 7 days in the SIMS Deltec
MEDICATION CASSETTE™ Reservoir‡.

Since limited compatibility
data are available, adherence to the recommended diluents and infusion systems
is advised. Solutions containing LEUSTATIN Injection should not be mixed with other
intravenous drugs or additives or infused simultaneously via a common
intravenous line, since compatibility testing has not been performed.
Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS).

Care must be taken to assure the sterility of prepared
solutions. Once diluted, solutions of LEUSTATIN Injection should be
administered promptly or stored in the refrigerator (2° to 8° C) for no more
than 8 hours prior to start of administration. Vials of LEUSTATIN Injection are
for single-use only. Any unused portion should be discarded in an appropriate
manner (see Handling and Disposal).

Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever solution
and container permit. A precipitate may occur during the exposure of LEUSTATIN
Injection to low temperatures; it may be resolubilized by allowing the solution
to warm naturally to room temperature and by shaking vigorously. DO NOT HEAT OR
MICROWAVE.

Chemical Stability of Vials

When stored in refrigerated conditions between 2° to 8°C
(36° to 46°F) protected from light, unopened vials of LEUSTATIN Injection are
stable until the expiration date indicated on the package. Freezing does not
adversely affect the solution. If freezing occurs, thaw naturally to room
temperature. DO NOT heat or microwave. Once thawed, the vial of LEUSTATIN
Injection is stable until expiry if refrigerated. DO NOT refreeze. Once
diluted, solutions containing LEUSTATIN Injection should be administered
promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours
prior to administration.

Handling and Disposal

The potential hazards associated with cytotoxic agents are
well established and proper precautions should be taken when handling,
preparing, and administering LEUSTATIN Injection. The use of disposable gloves
and protective garments is recommended. If LEUSTATIN Injection contacts the
skin or mucous membranes, wash the involved surface immediately with copious
amounts of water. Several guidelines on this subject have been published.2-8
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate. Refer to your Institution's guidelines
and all applicable state/local regulations for disposal of cytotoxic waste.

The following safety data are
based on 196 patients with Hairy Cell Leukemia: the original cohort of 124
patients plus an additional 72 patients enrolled at the same two centers after
the original enrollment cutoff. In Month 1 of the Hairy Cell Leukemia clinical
trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection
was documented in 28%. Most non-hematologic adverse experiences were mild to
moderate in severity.

Myelosuppression was frequently
observed during the first month after starting treatment. Neutropenia (ANC <
500 x 106/L) was noted in 70% of patients, compared with 26% in whom
it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in
37% of patients, compared with 10% initially and thrombocytopenia (Platelets
< 20 x 109/L) developed in 12% of patients, compared to 4% in
whom it was noted initially.

During the first month, 54 of 196
patients (28%) exhibited documented evidence of infection. Serious infections
(e.g., septicemia, pneumonia) were reported in 6% of all patients; the
remainder were mild or moderate. Several deaths were attributable to infection
and/or complications related to the underlying disease. During the second
month, the overall rate of documented infection was 6%; these infections were
mild to moderate and no severe systemic infections were seen. After the third
month, the monthly incidence of infection was either less than or equal to that
of the months immediately preceding LEUSTATIN therapy.

During the first month, 11% of patients experienced severe
fever (i.e., ≥ 104°F). Documented infections were noted in fewer than
one-third of febrile episodes. Of the 196 patients studied, 19 were noted to
have a documented infection in the month prior to treatment. In the month
following treatment, there were 54 episodes of documented infection: 23 (42%)
were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8
documented episodes of herpes zoster occurred during the month following
treatment. Fourteen (14) of 16 episodes of documented fungal infections
occurred in the first two months following treatment. Virtually all of these
patients were treated empirically with antibiotics. (see WARNINGS andPRECAUTIONS)

Analysis of lymphocyte subsets indicates that treatment with
cladribine is associated with prolonged depression of the CD4 counts. Prior to
treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which
occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15)
months after treatment, mean CD4 counts remained below 500/μL. CD8 counts
behaved similarly, though increasing counts were observed after 9 months. The
clinical significance of the prolonged CD4 lymphopenia is unclear.

Another event of unknown clinical significance includes the
observation of prolonged bone marrow hypocellularity. Bone marrow cellularity
of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the
two pivotal trials. This hypocellularity was noted as late as day 1010. It is
not known whether the hypocellularity is the result of disease related marrow
fibrosis or if it is the result of cladribine toxicity. There was no apparent
clinical effect on the peripheral blood counts.

The vast majority of rashes were mild. Most episodes of
nausea were mild, not accompanied by vomiting, and did not require treatment
with antiemetics. In patients requiring antiemetics, nausea was easily
controlled, most frequently with chlorpromazine.

When used in other clinical settings the following ADRs were
reported: bacteremia, cellulitis, localized infection, pneumonia, anemia,
thrombocytopenia (with bleeding or petechiae), phlebitis, purpura,
crepitations, localized edema and edema.

For a description of adverse reactions associated with use
of high doses in non-Hairy Cell Leukemia patients, see WARNINGS.

Postmarketing Experience

The following additional adverse reactions have been
reported since the drug became commercially available. These adverse reactions
have been reported primarily in patients who received multiple courses of
LEUSTATIN Injection:

Infections and infestations: Septic shock.
Opportunistic infections have occurred in the acute phase of treatment.

Skin and tissue disorders:Urticaria,
hypereosinophilia; Stevens-Johnson. In isolated cases toxic epidermal
necrolysis has been reported in patients who were receiving or had recently
been treated with other medications (e.g., allopurinol or antibiotics) known to
cause these syndromes.

DRUG INTERACTIONS

There are no known drug interactions with LEUSTATIN
Injection. Caution should be exercised if LEUSTATIN Injection is administered
before, after, or in conjunction with other drugs known to cause
immunosuppression or myelosuppression. (see WARNINGS)

Warnings

WARNINGS

Due to increased risk of infection in the setting of
immunosuppression with chemotherapy including LEUSTATIN, it is recommended not
to administer live attenuated vaccines to patients receiving LEUSTATIN
Injection.

Severe bone marrow suppression, including neutropenia,
anemia and thrombocytopenia, has been commonly observed in patients treated
with LEUSTATIN, especially at high doses. At initiation of treatment, most
patients in the clinical studies had hematologic impairment as a manifestation
of active Hairy Cell Leukemia. Following treatment with LEUSTATIN, further
hematologic impairment occurred before recovery of peripheral blood counts
began. During the first two weeks after treatment initiation, mean Platelet
Count, ANC, and Hemoglobin concentration declined and subsequently increased
with normalization of mean counts by Day 12, Week 5 and Week 8, respectively.
The myelosuppressive effects of LEUSTATIN were most notable during the first
month following treatment. Forty-four percent (44%) of patients received
transfusions with RBCs and 14% received transfusions with platelets during
Month 1. Careful hematologic monitoring, especially during the first 4 to 8
weeks after treatment with LEUSTATIN Injection, is recommended (see PRECAUTIONS).

Fever (T ≥ 100°F) was associated with the use of
LEUSTATIN in approximately two-thirds of patients (131/196) in the first month
of therapy. Virtually all of these patients were treated empirically with
parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the
setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with
severe neutropenia (i.e., ANC ≤ 500).

In a Phase I investigational study using LEUSTATIN in high
doses (4 to 9 times the recommended dose for Hairy Cell Leukemia) as part of a
bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide
and total body irradiation, acute nephrotoxicity and delayed onset
neurotoxicity were observed. Thirty-one (31) poor-risk patients with
drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2
cases) received LEUSTATIN for 7 to 14 days prior to bone marrow
transplantation. During infusion, 8 patients experienced gastrointestinal
symptoms. While the bone marrow was initially cleared of all hematopoietic
elements, including tumor cells, leukemia eventually recurred in all treated
patients. Within 7 to 13 days after starting treatment with LEUSTATIN, 6
patients (19%) developed manifestations of renal dysfunction (e.g., acidosis,
anuria, elevated serum creatinine, etc.) and 5 required dialysis. Several of
these patients were also being treated with other medications having known
nephrotoxic potential. Renal dysfunction was reversible in 2 of these patients.
In the 4 patients whose renal function had not recovered at the time of death,
autopsies were performed; in 2 of these, evidence of tubular damage was noted.
Eleven (11) patients (35%) experienced delayed onset neurologic toxicity. In
the majority, this was characterized by progressive irreversible motor weakness
(paraparesis/quadriparesis) of the upper and/or lower extremities, first noted
35 to 84 days after starting high dose therapy with LEUSTATIN. Non-invasive
testing (electromyography and nerve conduction studies) was consistent with
demyelinating disease. Severe neurologic toxicity has also been noted with high
doses of another drug in this class.

Axonal peripheral polyneuropathy was observed in a dose escalation
study at the highest dose levels (approximately 4 times the recommended dose
for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total
body irradiation. Severe neurological toxicity has been reported rarely
following treatment with standard cladribine dosing regimens.

In patients with Hairy Cell Leukemia treated with the
recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there
have been no reports of nephrologic toxicities.

Of the 196 Hairy Cell Leukemia patients entered in the two
trials, there were 8 deaths following treatment. Of these, 6 were of infectious
etiology, including 3 pneumonias, and 2 occurred in the first month following
LEUSTATIN therapy. Of the 8 deaths, 6 occurred in previously treated patients
who were refractory to α interferon.

Benzyl alcohol is a constituent of the recommended diluent
for the 7-day infusion solution. Benzyl alcohol has been reported to be
associated with a fatal “Gasping Syndrome” in premature infants. (see
DOSAGE AND ADMINISTRATION)

Pregnancy Category D

LEUSTATIN can cause fetal harm when administered to a
pregnant woman. Although there is no evidence of teratogenicity in humans due
to LEUSTATIN, other drugs which inhibit DNA synthesis have been reported to be
teratogenic in humans. Cladribine is teratogenic in animals. Advise females of
reproductive potential to use highly effective contraception during treatment
with LEUSTATIN. If LEUSTATIN is used during pregnancy, or if the patient
becomes pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus.

Cladribine is teratogenic in mice and rabbits and
consequently has the potential to cause fetal harm when administered to a
pregnant woman. A significant increase in fetal variations was observed in mice
receiving 1.5 mg/kg/day (4.5 mg/m2) and increased resorptions,
reduced litter size and increased fetal malformations were observed when mice
received 3.0 mg/kg/day (9 mg/m2). Fetal death and malformations were
observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m2). No
fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m2) or in
rabbits at 1.0 mg/kg/day (11.0 mg/m2).

Precautions

PRECAUTIONS

General

LEUSTATIN Injection is a potent antineoplastic agent with
potentially significant toxic side effects. It should be administered only
under the supervision of a physician experienced with the use of cancer
chemotherapeutic agents. Patients undergoing therapy should be closely observed
for signs of hematologic and non-hematologic toxicity. Periodic assessment of
peripheral blood counts, particularly during the first 4 to 8 weeks
post-treatment, is recommended to detect the development of anemia, neutropenia
and thrombocytopenia and for early detection of any potential sequelae (e.g.,
infection or bleeding). As with other potent chemotherapeutic agents,
monitoring of renal and hepatic function is also recommended, especially in
patients with underlying kidney or liver dysfunction (see WARNINGS and ADVERSE
REACTIONS).

Fever was a frequently observed side effect during the first
month on study. Since the majority of fevers occurred in neutropenic patients,
patients should be closely monitored during the first month of treatment and
empiric antibiotics should be initiated as clinically indicated. Although 69%
of patients developed fevers, less than 1/3 of febrile events were associated
with documented infection. Given the known myelosuppressive effects of LEUSTATIN,
practitioners should carefully evaluate the risks and benefits of administering
this drug to patients with active infections (see WARNINGS and ADVERSE
REACTIONS).

There are inadequate data on dosing of patients with renal
or hepatic insufficiency. Development of acute renal insufficiency in some
patients receiving high doses of LEUSTATIN has been described. Until more
information is available, caution is advised when administering the drug to
patients with known or suspected renal or hepatic insufficiency (see WARNINGS).

Rare cases of tumor lysis syndrome have been reported in
patients treated with cladribine with other hematologic malignancies having a
high tumor burden.

LEUSTATIN Injection must be diluted in designated
intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION).

Laboratory Tests

During and following treatment, the patient's hematologic
profile should be monitored regularly to determine the degree of hematopoietic
suppression. In the clinical studies, following reversible declines in all cell
counts, the mean Platelet Count reached 100 x 109/L by Day 12, the
mean Absolute Neutrophil Count reached 1500 x 106/L by Week 5 and
the mean Hemoglobin reached 12 g/dL by Week 8.

After peripheral counts have normalized, bone marrow
aspiration and biopsy should be performed to confirm response to treatment with
LEUSTATIN. Febrile events should be investigated with appropriate laboratory
and radiologic studies. Periodic assessment of renal function and hepatic
function should be performed as clinically indicated.

Carcinogenesis

No animal carcinogenicity studies have been conducted with
cladribine. However, its carcinogenic potential cannot be excluded based on
demonstrated genotoxicity of cladribine.

Mutagenesis

As expected for compounds in this class, the actions of
cladribine yield DNA damage. In mammalian cells in culture, cladribine caused
the accumulation of DNA strand breaks. Cladribine was also incorporated into
DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in
vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not
induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However,
cladribine was clastogenic both in vitro (chromosome aberrations in Chinese
hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).

Impairment of Fertility

The effect on human fertility is unknown. When administered
intravenously to Cynomolgus monkeys, cladribine has been shown to cause
suppression of rapidly generating cells, including testicular cells.

Pregnancy

Pregnancy Category D: (see WARNINGS).

Nursing Mothers

It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from cladribine, a decision should
be made whether to discontinue nursing or discontinue the drug, taking into
account the importance of the drug for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been
established. In a Phase I study involving patients 1-21 years old with relapsed
acute leukemia, LEUSTATIN was given by continuous intravenous infusion in doses
ranging from 3 to 10.7 mg/m2/day for 5 days (one-half to twice the
dose recommended in Hairy Cell Leukemia). In this study, the dose-limiting
toxicity was severe myelosuppression with profound neutropenia and
thrombocytopenia. At the highest dose (10.7 mg/m2/day), 3 of 7
patients developed irreversible myelosuppression and fatal systemic bacterial
or fungal infections. No unique toxicities were noted in this study1
(see WARNINGS and ADVERSE REACTIONS).

Geriatric Use

Clinical studies of LEUSTATIN did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy in elderly patients.

OVERDOSE

High doses of LEUSTATIN have been associated with:
irreversible neurologic toxicity (paraparesis/quadriparesis), acute
nephrotoxicity, and severe bone marrow suppression resulting in neutropenia,
anemia and thrombocytopenia (see WARNINGS). There is no known specific
antidote to overdosage. Treatment of overdosage consists of discontinuation of
LEUSTATIN, careful observation and appropriate supportive measures. It is not
known whether the drug can be removed from the circulation by dialysis or
hemofiltration.

CONTRAINDICATIONS

LEUSTATIN Injection is contraindicated in those patients who
are hypersensitive to this drug or any of its components.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Cellular Resistance and Sensitivity

The selective toxicity of
2-chloro-2'-deoxy-β-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of
deoxycytidine kinase and deoxynucleotidase. Cladribine passively crosses the
cell membrane. In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase,
it is phosphorylated by deoxycytidine kinase to 2-chloro-2'-deoxy-β
-D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2'-deoxy-β
-D-adenosine is resistant to deamination by adenosine deaminase and there is
little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP
accumulates intracellularly and is subsequently converted into the active
triphosphate deoxynucleotide, 2-chloro-2'-deoxy-β -D-adenosine
triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase
and low deoxynucleotidase activities will be selectively killed by
2-chloro-2'-deoxy-β -D-adenosine as toxic deoxynucleotides accumulate
intracellularly.

Cells containing high concentrations of deoxynucleotides are
unable to properly repair single-strand DNA breaks. The broken ends of DNA
activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP
depletion and disruption of cellular metabolism. There is evidence, also, that
2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment
of DNA synthesis. Thus, 2-chloro-2'-deoxy-β -D-adenosine can be
distinguished from other chemotherapeutic agents affecting purine metabolism in
that it is cytotoxic to both actively dividing and quiescent lymphocytes and
monocytes, inhibiting both DNA synthesis and repair.

Pharmacokinetics

In a clinical investigation, 17 patients with Hairy Cell
Leukemia and normal renal function were treated for 7 days with the recommended
treatment regimen of LEUSTATIN Injection (0.09 mg/kg/day) by continuous
intravenous infusion. The mean steady-state serum concentration was estimated
to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when
LEUSTATIN was given by continuous infusion over 7 days. In Hairy Cell Leukemia
patients, there does not appear to be a relationship between serum concentrations
and ultimate clinical outcome.

In another study, 8 patients with hematologic malignancies
received a two (2) hour infusion of LEUSTATIN Injection (0.12 mg/kg). The mean
end-of-infusion plasma LEUSTATIN concentration was 48±19 ng/mL. For 5 of these
patients, the disappearance of LEUSTATIN could be described by either a
biphasic or triphasic decline. For these patients with normal renal function,
the mean terminal half-life was 5.4 hours. Mean values for clearance and
steady-state volume of distribution were 978±422 mL/h/kg and 4.5±2.8 L/kg,
respectively.

Cladribine plasma concentration after intravenous
administration declines multi-exponentially with an average half-life of 6.7
+/- 2.5 hours. In general, the apparent volume of distribution of cladribine is
approximately 9 L/kg, indicating an extensive distribution in body tissues.

Cladribine penetrates into cerebrospinal fluid. One report
indicates that concentrations are approximately 25% of those in plasma.

LEUSTATIN is bound approximately 20% to plasma proteins.

Except for some understanding of the mechanism of cellular
toxicity, no other information is available on the metabolism of LEUSTATIN in
humans. An average of 18% of the administered dose has been reported to be
excreted in urine of patients with solid tumors during a 5-day continuous
intravenous infusion of 3.5-8.1 mg/m2/day of LEUSTATIN. The effect
of renal and hepatic impairment on the elimination of cladribine has not been
investigated in humans.

Clinical Studies

Two single-center open label studies of LEUSTATIN
(cladribine) have been conducted in patients with Hairy Cell Leukemia with
evidence of active disease requiring therapy. In the study conducted at the
Scripps Clinic and Research Foundation (Study A), 89 patients were treated with
a single course of LEUSTATIN Injection given by continuous intravenous infusion
for 7 days at a dose of 0.09 mg/kg/day. In the study conducted at the M.D.
Anderson Cancer Center (Study B), 35 patients were treated with a 7-day
continuous intravenous infusion of LEUSTATIN Injection at a comparable dose of
3.6 mg/m2/day. A complete response (CR) required clearing of the
peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin
to 12 g/dL, platelet count to 100 x 109/L, and absolute neutrophil
count to 1500 x 106/L. A good partial response (GPR) required the
same hematologic parameters as a complete response, and that fewer than 5%
hairy cells remain in the bone marrow. A partial response (PR) required that
hairy cells in the bone marrow be decreased by at least 50% from baseline and
the same response for hematologic parameters as for complete response. A
pathologic relapse was defined as an increase in bone marrow hairy cells to 25%
of pretreatment levels. A clinical relapse was defined as the recurrence of
cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥
25% or platelet counts ≥ 50,000. Patients who met the criteria for a
complete response but subsequently were found to have evidence of bone marrow
hairy cells ( < 25% of pretreatment levels) were reclassified as partial
responses and were not considered to be complete responses with relapse.

Among patients evaluable for efficacy (N=106), using the
hematologic and bone marrow response criteria described above, the complete
response rates in patients treated with LEUSTATIN Injection were 65% and 68%
for Study A and Study B, respectively, yielding a combined complete response
rate of 66%. Overall response rates (i.e., Complete plus Good Partial plus
Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a
combined overall response rate of 88% in evaluable patients treated with
LEUSTATIN Injection.

Using an intent-to-treat analysis (N=123) and further
requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and ≤ 13 cm on CT scan), the complete
response rates for Study A and Study B were 54% and 53%, respectively, giving a
combined CR rate of 54%. The overall response rates (CR + GPR + PR) were 90%
and 85%, for Studies A and B, respectively, yielding a combined overall
response rate of 89%.

In these studies, 60% of the
patients had not received prior chemotherapy for Hairy Cell Leukemia or had
undergone splenectomy as the only prior treatment and were receiving LEUSTATIN
as a first-line treatment. The remaining 40% of the patients received LEUSTATIN
as a second-line treatment, having been treated previously with other agents,
including α-interferon and/or deoxycoformycin. The overall response rate
for patients without prior chemotherapy was 92%, compared with 84% for
previously treated patients. LEUSTATIN is active in previously treated
patients; however, retrospective analysis suggests that the overall response
rate is decreased in patients previously treated with splenectomy or deoxycoformycin
and in patients refractory to α-interferon.

After a reversible decline,
normalization of peripheral blood counts (Hemoglobin > 12.0 g/dL, Platelets
> 100 x 109/L, Absolute Neutrophil Count (ANC) > 1500 x 106/L)
was achieved by 92% of evaluable patients. The median time to normalization of
peripheral counts was 9 weeks from the start of treatment (Range: 2 to 72). The
median time to normalization of Platelet Count was 2 weeks, the median time to
normalization of ANC was 5 weeks and the median time to normalization of
Hemoglobin was 8 weeks. With normalization of Platelet Count and Hemoglobin,
requirements for platelet and RBC transfusions were abolished after Months 1
and 2, respectively, in those patients with complete response. Platelet
recovery may be delayed in a minority of patients with severe baseline
thrombocytopenia. Corresponding to normalization of ANC, a trend toward a
reduced incidence of infection was seen after the third month, when compared to
the months immediately preceding LEUSTATIN therapy. (see also WARNINGS, PRECAUTIONS
and ADVERSE REACTIONS)

LEUSTATIN TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA
TIME TO NORMALIZATION OF PERIPHERAL BLOOD COUNTS

Parameter

Median Time to Normalization of Count*

Platelet Count

2 weeks

Absolute Neutrophil Count

5 weeks

Hemoglobin

8 weeks

ANC, Hemoglobin and Platelet Count

9 weeks

* Day 1 = First day of infusion

For patients achieving a complete
response, the median time to response (i.e., absence of hairy cells in bone
marrow and peripheral blood together with normalization of peripheral blood
parameters), measured from treatment start, was approximately 4 months. Since
bone marrow aspiration and biopsy were frequently not performed at the time of
peripheral blood normalization, the median time to complete response may
actually be shorter than that which was recorded. At the time of data cut-off,
the median duration of complete response was greater than 8 months and ranged
to 25+ months. Among 93 responding patients, seven had shown evidence of
disease progression at the time of the data cut-off. In four of these patients,
disease was limited to the bone marrow without peripheral blood abnormalities
(pathologic progression), while in three patients there were also peripheral
blood abnormalities (clinical progression). Seven patients who did not respond
to a first course of LEUSTATIN received a second course of therapy. In the five
patients who had adequate follow-up, additional courses did not appear to
improve their overall response.